While novel targets are essential to new approaches to pain, addiction, and overdose, modulating those novel targets frequently requires novel chemical structures, the production of which remains arduous and slow inadequate to the imperatives of the opioid crisis. An automated solution to this problem, termed A Specialized Platform for Innovative Research Execution (ASPIRE), has been under development at NCATS with its collaborators and will be deployed to address the opioid crisis. ASPIRE aims to combine automated synthetic chemistry (ASC), AI, and biological testing; and catalyze the bridging of chemical biology and pharmacology into pre-clinical drug discovery. This existing initiative will solve longstanding, previously intractable problems in chemistry by enabling (a) synthesis of biologically relevant libraries of diverse compounds with minimal human intervention; (b) prediction of the effect of synthesized chemical compounds on biological function and/or structure; (c) development of new tools and technologies to achieve fully automated synthesis (AS); and (d) systematic development of better and more effective therapies through AS. ASPIRE will develop novel, safer opioids and non-opioid analgesics using synthetic chemistry approaches to target pain, addiction and overdose. Existing data on the structure of currently available pain drugs will be analyzed to identify, for example, side groups that are less likely to trigger addiction. This data will be used as a training set to design, synthesize, optimize, and test novel compounds that are less likely to trigger addiction. By utilizing existing collaborative mechanisms and resources at NCATS, optimized novel small molecule leads would be tested for their bioactivity at the NCATS high throughput screening (HTS) facility using physiologically relevant models such as iPSC-derived human sensory neuronal cultures to provide proof-of-concept for therapeutic hypotheses to treat pain, addiction and overdose.